20 replies to this topic

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Agmatine

"Agmatine has been discussed as a putative neurotransmitter/neuromodulator. It is synthesized in the brain, stored in synaptic vesicles, accumulated by uptake, released by membrane depolarization, and inactivated by agmatinase. Agmatine binds to α2-adrenergic receptor and imidazoline receptor binding sites, and blocks NMDA receptors and other cation ligand-gated channels. Short only of identifying specific ("own") post-synaptic receptors, agmatine in fact, fulfills Henry Dale's criteria for a neurotransmitter and is hence, considered a neuromodulator and co-transmitter. But identification of agmatinergic neuronal systems, if exist, still awaits future research."

"Agmatine has several mechanisms. It can inhibit N-methyl-D-aspartate (NMDA) and nicotinic acetylcholine receptors, as well as activate imidazoline receptors. Agmatine can also inhibit nitric oxide synthase enzymes, which allows it to regulate elevated levels of nitric oxide. Agmatine can inhibit calcium channels and certain serotonin receptors as well. Further research is needed to determine the full extent of agmatines mechanisms."

3.9. Opioidergic Neurotransmission

The activation of imidazoline receptors (specifically I2 receptors) in the adrenal glands appears to induce the release of β-endorphin (a naturally produced opioidergic pain killer)[92] which has central and peripheral implications.

Enhancement of opioidergic analgesia[123] and the attenuation of tolerance development[141] have been noted with NMDA antagonists before (possible role of Agmatine) although one study has noted that the prevention of tolerance was reliant on activation of imidazoline receptors.[142]

Agmatine is able to release some opioids inherently by activating imidazoline receptors in the adrenal glands. So in regards to the following information of how agmatine interacts with opioids (which should apply to β-endorphin as well), it is somewhat synergistic with itself in persons with functioning adrenals
The acute analgesic (pain killing) effects of morphine are augmented when coadministered with agmatine,[143] which is mediated by α2A receptors[144] and appears to extend to oxycodone[145] and fentanyl (two other opioidergic drugs similar to morphine).

For acute analgesia, agmatine appears to be synergistic with opioids
Agmatine has been found to potently inhibit tolerance to μ-opioid agonists (Endo-2 and DAMGO-AG) with intrathecal injections of 4nmol[112] which appears to be effective for up to 48 hours following a single dose.[112] This has also been noted in rhesus monkeys given oral agmatine (40-80mg/kg).[146]

Tolerance to opioidergic drugs has been noted to be reduced in research animals.[143][120]

Tolerance to opioids (the reduction of efficacy that comes with prolonged usage) appears to be attenuated when agmatine is coadministered, which would synergistically preserve the analgesic effects of opioids
Adrenergic receptors are involved with opioid receptors, with activation of the α2A receptor[147][148] and inhibition of β-adrenergic receptors being able to attenuate morphine withdrawal symptoms;[149] conversely, Yohimbine (inhibitor of α2A) negatively augments withdrawal symptoms.[150][151]

In studies that measure addictive properties (self-administration usually what is investigated) or withdrawal symptoms of opioidergic drugs, agmatine has been noted to reduce self-administration of fentanyl.[152][153]

In regards to conditioned place preference (CPP; a preference for one place over another thought to be a biomarker of addictive behaviour[154]), agmatine cotreatment with morphine is able to augment morphine-induced conditioned place preference.[155]

3.18. Calcium signalling

Agmatine has a few interactions with calcium signalling. Firstly, NMDA receptor activation tends to increase intracellular calcium which can then activate nNOS[266][267] and via being an NDMA antagonist[105] agmatine can limit the increase in calcium (agmatine can act on nNOS in more than just this way, however). Furthermore, agmatine has been noted to block calcium channels directly on hippocampal neurons in a reversible manner with an IC50 value of 0.79-1.57µM and recorded 21+/-4% inhibition at a concentration of 100nM[225] but elsewhere has been noted to displace the calcium channel blocker known as Diltiazem.[268]

Agmatine has failed to have any influence on sodium or potassium channels at concentrations of up to 500µM.[225] That being said, nitric oxide has been noted to increase the activity of calcium-activated potassium channels[269][270] which is downstream of NMDA activation;[271] this presumes an inhibitory effect of agmatine on potassium channels (as it is an NMDA antagonist), which is thought to at least in part contribute to antidepressant effects.[215]


I'm taking 1.5 grams agmatine in this stack a day minimum

Huperazine a:

Pharmacological effects[edit]
Huperzine A is extracted from Huperzia serrata.[1] It is an acetylcholinesterase inhibitor[4][5] and NMDA receptor antagonist.[6] The structure of the complex of huperzine A with acetylcholinesterase has been determined by X-ray crystallography (PDB code: 1VOT; see the 3D structure).[7]

Neuroscience. 2001;105(3):663-9.
Huperzine A, a nootropic alkaloid, inhibits N-methyl-D-aspartate-induced current in rat dissociated hippocampal neurons.
Zhang JM1, Hu GY.
Author information

Abstract
Huperzine A, a nootropic alkaloid isolated from a Chinese herb, has been proposed as one of the most promising agents to treat Alzheimer's disease. Recently, the agent was found to inhibit the N-methyl-D-aspartate (NMDA) receptors in rat cerebral cortex in addition to causing an inhibitory effect on acetylcholinesterase. In the present study, the mechanisms underlying NMDA receptor inhibition were investigated using whole-cell voltage-clamp recording in CA1 pyramidal neurons acutely dissociated from rat hippocampus. Huperzine A reversibly inhibited the NMDA-induced current (IC(50)=126 microM, Hill coefficient=0.92), whereas it had no effect on the current induced by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate or kainate. The effect was non-competitive, and showed neither 'voltage-dependency', nor 'use-dependency'. The IC(50) values of huperzine A were neither altered by changing the concentrations of glycine (2-0.2 microM) and pH (7.4-6.7) in the external solution, nor by addition of Zn(2+) (5 microM) and dithiothreitol (5 mM) to the external solution. However, addition of spermine (200 microM) to the external solution caused a parallel shift to the right of the huperzine A concentration-response curve. From these we suggest that huperzine A acts as a non-competitive antagonist of the NMDA receptors, via a competitive interaction with one of the polyamine binding sites. The potential relevance of NMDA receptor antagonist activity of huperzine A to the treatment of Alzheimer's disease is discussed.

Huperzine A is a non-competitive antagonist of NMDA receptors [2] via negative allosteric modulation of the MK-801 binding site [4]. Unlike memantine, hup A's NMDA antagonism is not use- or voltage-dependent [2],


Keywords:
huperzine A;glutamate;NMDA;calcium;protection;ion channel;PCP;cholinesterase;receptors;neuroprotection
Abstract
Huperzine A (HUP-A), first isolated from the Chinese club moss Huperzia serrata, is a potent, reversible and selective inhibitor of acetylcholinesterase (AChE) over butyrylcholinesterase (BChE) (Life Sci. 54: 991997). Because HUP-A has been shown to penetrate the bloodbrain barrier, is more stable than the carbamates used as pretreatments for organophosphate poisoning (OP) and the HUP-A:AChE complex has a longer half-life than other prophylactic sequestering agents, HUP-A has been proposed as a pretreatment drug for nerve agent toxicity by protecting AChE from irreversible OP-induced phosphonylation. More recently (NeuroReport8: 963968), pretreatment of embryonic neuronal cultures with HUP-A reduced glutamate-induced cell death and also decreased glutamate-induced calcium mobilization. These results suggest that HUP-A might interfere with and be beneficial for excitatory amino acid overstimulation, such as seen in ischemia, where persistent elevation of internal calcium levels by activation of the N-methyl-d-aspartate (NMDA) glutamate subtype receptor is found. We have now investigated the interaction of HUP-A with glutamate receptors. Freshly frozen cortex or synaptic plasma membranes were used, providing 6090% specific radioligand binding. Huperzine A (≤100 µM) had no effect on the binding of [3H]glutamate (low- and high-affinity glutamate sites), [3H]MDL 105,519 (NMDA glycine regulatory site), [3H]ifenprodil (NMDA polyamine site) or [3H]CGS 19755 (NMDA antagonist). In contrast with these results, HUP-A non-competitively (Hill slope < 1) inhibited [3H]MK-801 and [3H]TCP binding (co-located NMDA ion channel PCP site) with pseudo Ki ∼ 6 µM. Furthermore, when neuronal cultures were pretreated with HUP-A for 45 min prior to NMDA exposure, HUP-A dose-dependently inhibited the NMDA-induced toxicity. Although HUP-A has been implicated to interact with cholinergic receptors, it was without effect at 100 µM on muscarinic (measured by inhibition of [3H]QNB or [3H]NMS binding) or nicotinic [3H]epibatidine binding) receptors; also, HUP-A did not perturb adenosine receptor binding [3H]PIA or [3H]NECA). Therefore, HUP-A most likely attenuates excitatory amino acid toxicity by blocking the NMDA ion channel and subsequent Ca2+ mobilization at or near the PCP and MK-801 ligand sites. Thus, on the one hand, HUP-A could be used as a pretreatment against OPs and it might also be a valuable therapeutic intervention in a variety of acute and chronic disorders by protecting against overstimulation of the excitatory amino acid pathway. By blocking NMDA ion channels without psychotomimetic side-effects, HUP-A may protect against diverse neurodegenerative states observed during ischemia or Alzheimer's disease. Copyright © 2001 John Wiley & Sons, Ltd.

I'm taking 200 mcg huperazine-a Bid with 500 mg Agmatine Tid along with 2048mg magnesium l threonate and , 120 mg (pm only) Lithium orotate too complete my stack , will post evidence of magteins superior nmda modulation and inhibition






[11]

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Magtein or magnesium l threonate :

2. Kinetics and the Blood Brain Barrier

Magnesium concentration in the brain is higher than that of serum, with a homeostatic balance achieved at the blood-brain barrier maintained by active transport; at least one study that elevated serum Magnesium with intravenous Magnesium Sulfate failed to find such alterations in neural concentrations of Magnesium,[66] with increases of 100-300% in serum correlating roughly 10-19%.[67] This has been noted elsewhere, where supraphysiological concentrations of Magnesium increased neural stores merely 11-18%.[68]

One study assessing Magnesium L-Threonate (MgT), said to increase neural concentrations of Magnesium to a greater degree than other forms (all forms standardized to 50mg Magnesium), noted that while Magnesium Gluconate and Magnesium Citrate were able to normalize Magnesium levels (which appeared to decline at day 24 in control mice, as measuring cerebrospinal fluid reduced Magnesium inherently), Magnesium L-Threonate caused elevations at day 12 and 24; the degree of increase was slightly less than 10%, but corrected to approximately 15% when taking measurement into consideration.[55] Only one other study currently has assessed Magnesium L-Threonate but did not measure cerebrospinal concentrations,[69] so currently higher doses of MgT causing higher levels of neural Magnesium stores has not yet been evaluated.

There appears to be a rate limit that occurs in the 11-18% range with magnesium superloading on the brain, and this can be mimicked with low dose supplementation of Magnesium L-Threonate (50mg Magnesium, 604mg total). Magnesium L-Threonate has not yet been tested in humans, and no dose-dependency study has been conducted

3.3. ADHD

Magnesium deficiency may be more common in children with diagnosed ADHD, with one study of 116 children noting a deficiency rate of 95%[70] and another study noting a reduced Magnesium content in the saliva of children with ADHD relative to control children, where control saliva had a concentration of 0.70+/-0.2mmol/L and ADHD had a concentration of 0.23+/-0.06mmol/L.[71] At least one study dividing children into subgroups of ADD and ADHD (with the difference being the presence of hyperactivity) noted that Magnesium deficiency only occurred in the hyperactive subgroup and not the inattentive group or control.[72]

Subsequently, an intervention of 50 diagnosed children (7-12yrs) with ADHD and dietary magnesium deficiency, there was a significant improvement in hyperactivity (relative to baseline) as assessed by two rating scales in response to daily ingestion of 200mg Magnesium over 6 months.[73] These benefits may be augmented by Fish Oil omega 3 fatty acids, as evidenced by one cohort of 810 children followed for 12 weeks that showed benefit to symptoms as assessed by SNAP-IV (a rating scale different from the one in the previous study).[74]

Currently, there is some evidence for Magnesium being of use to children with ADHD as ADHD may be related to Magnesium deficiency. There is not enough evidence to assess the potency



Also

Edit3. Neurology and the Brain

3.1. Mechanisms

The main neuronal mechanism of Magnesium ions in the brain is that of an inhibitory ion to counteract calcium at NMDA receptors,[47][48] excitatory receptors involved in long-term learning and excitation; Magnesium exists as an endogenous calcium channel blocker[49] and is regulatory of calcium metabolism.[50][51] Low Magnesium levels are associated with neuronal hyperexcitation and random firing, and secondary to higher activation of NMDA receptors more calcium appears to be released.[52]

At resting membrane potential (when neurons are not directed to fire) magnesium occupies these ion channels and prevents activation of neurons,[53][54] while activation of neurons intentionally displaces magnesium;[55] making Magnesium at normal concentrations not necessarily inhibitory but more of a placeholder, although it can exert antagonistic effects when superloaded.[56][57] Drugs that do not get displaced during neuronal activation, and effectively block activation via NMDA, include Memantine[53] and Ketamine.[58]

Acute regulation of Magnesium is highly regulated both by sets of ionic pumps on neurons[59] and the choroid plexus, which acts in concert with the blood brain barrier to establish a constant concentration of Magensium.[59][60][61] Decreases in cerebral Magnesium stores are only seen over prolonged periods of inadequate Magnesium ingestion.[62]

Magnesium is critical to preserving neuronal functon during periods of downtime, when the neuron is not firing. A deficiency of Magnesium in the brain (which tends to only occur during chronic deprivation of dietary magnesium) makes cells have more activation during periods where they are not intentionally activated
And.....

Increased Brain Cell Signaling
The first step was to determine the effects of MgT supplementation on signaling between brain cells mediated by what are known as NMDA receptors. These receptors operate through varying concentrations of calcium and magnesium in brain tissue, making them a logical point of observation.

The first finding was that MgT treatment in animals resulted in stronger signaling at essential brain cell synapses.8 This increase in signaling was accomplished by a 60% increase in production of new NMDA receptors and by increases of up to 92% in related proteins that play essential supporting roles in brain signal transmission.8

Higher Memory- Forming Synaptic Plasticity and Density
Synaptic plasticity, or the ability to rapidly change the number and strength of brain cell synapses, is critical to the brain's ability to form, retain, and retrieve memories. The research team compared synaptic plasticity in the brains of MgT-supplemented animals versus controls.8

They found that production of a very special subunit of the NMDA receptor, one closely associated with synaptic plasticity, was selectively enhanced by MgT supplementation.8 This molecular change is known to cause potent long-term increases in synaptic strength, and hence a greater capacity for information storage and memory.8,24-26

The result of these increases in NMDA receptor numbers was a 52% enhancement in long-term potentiation,8 which is the cellular equivalent of memory formation in the brain tissues of MgT-supplemented animals.27,28

Memory depends not only on synaptic plasticity, but also on the healthy physical structure of synapses between brain cells. Unfortunately, synaptic connections in the memory-rich hippocampus region of the brain decline with aging, which directly correlates with memory loss.8,29,30,31

One of the most vital structures to be found at brain cell synapses is the synaptic bouton, from the French word for button. When an electrical impulse reaches a pre-synaptic bouton, and ample calcium and magnesium are present, neurotransmitters are released to transmit the impulse to the next neuron in line. The greater the number and density of synaptic boutons, the stronger the electrochemical signal that the synapse can produce, and the more sustained the memory that is created.32

When the researchers examined the brains of control and MgT-supplemented animals under a high-power microscope, they readily detected much greater densities of synaptic bouton proteins in tissues from the supplemented animals. Those proteins are essential for neurotransmitter release in the several regions of the hippocampus vital for memory formation and retrieval.8 Remarkably, the density of the synaptic boutons was closely correlated with the memory performance of each individual animal on the novel object recognition test


.....

One of the critical factors for establishing E-LTP is the availability and proper functioning of NMDA receptors and their activation by neurotransmitters. NMDA receptors are the channels by which calcium ion influx to the cell occurs in response to the right sequence of action potentials. This calcium influx leads to activation of the enzymes PKC and CAMKII which further activate NMDA receptors and, through a signaling cascade, promote AMPA receptors to the synaptic cleft in a process critical to E-LTP [2].

Magnesium Threonate (MgT) has been shown in studies to enhance E-LTP via increasing the amount of NR2B NMDA receptors in the synaptic cleft [3]. Additionally, MgT treatment has been show to increase the number of synaptophysin/synaptobrevin positive puncta in neurons. Synaptophysin and synaptobrevin are two proteins that are critical to the neurons ability to store and transport neurotransmitters for release into the synaptic cleft. Increasing the levels of these proteins in neurons can positively affect neurotransmitter signaling between neurons.

Studies have shown that brain magnesium might also affect L-LTP through an indirect mechanism. A recent study in an animal model found that magnesium ions interacting with NMDA receptors were necessary for long-term memory formation but not associative learning. The study found that magnesiums interaction with NMDA receptors suppressed a CREB repressor protein, thus facilitating CREB-dependent gene expression [4]. CREB is a transcription factor that when activated causes the nucleus and the mitochondria to transcribe proteins that cause growth of the neuron and L-LTP [5]. Thus, facilitating CREBs ability to induce gene-expression by blocking a CREB repressor protein, as magnesium does in this instance, can aid the process of L-LTP.

Studies have suggested that MgT can positively affect aspects of the brain that become dysfunctional due to disease or stress. A way that NMDA receptors can become dysfunctional is due to TNF-alpha (TNF-α) overexpression, usually as a result of chronic or neuropathic pain. Research suggests that this can disrupt short term memory. In a recent study MgT was shown to be helpful in reducing the disruption to NMDAR function possibly via normalization of TNF-α expression [6].

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Lithium orotate:

Lithium and Alzheimers: New hope for a hopeless situation

As you know, theres no cure for Alzheimers disease and theres very little available for patients (and families) that can offer even partial relief from the turmoil it causes. So when new treatments are developed or discovered, its usually big news -a ray of hope for people stuck in a seemingly hopeless situation. One of these newly developed patent medications, called Memantine,™ was recently approved in Europe. Even though its not officially approved in this country (yet), thousands of people are already importing Memantine to the U.S. via various Internet sources. But why go through all the trouble (not to mention risk) of getting and using this new patent formula? Apparently, it works by protecting brain cells against damage caused by a major excitotoxin, glutamate. But protecting against glutamate-induced nerve cell damage is also one of the well-known actions of lithium. So if its true that this newly approved patent medication slows the progress of Alzheimers disease in this way, then lithium should slow Alzheimers disease progression, too. Of course, lithium treatment, which isnt patentable and doesnt have nearly the profit potential of patented Alzheimers medications, hasnt made any headlines. But that doesnt mean it isnt a promising option for patients struggling with Alzheimers disease.

There are many other research findings that also strongly suggest that lithium will protect against potential Alzheimers disease and slow the progression of existing cases. Researchers have reported that lithium inhibits beta-amyloid secretion, and also prevents damage caused by beta-amyloid protein once its been formed.20-23 Beta-amyloid peptide is a signature protein involved in Alzheimers disease: the more beta-amyloid protein, the worse the Alzheimers becomes.

Overactivation of a brain cell protein called tau protein also contributes to neuronal degeneration in Alzheimers disease, as does the formation of neurofibrillary tangles Lithium inhibits both of these nerve-cell damaging problems.24,25

And youve likely read that individuals with Alzheimers disease usually have excess aluminum accumulation in brain cells. While its not yet known whether this excess aluminum is a cause, an effect, or just coincidental, most health-conscious individuals take precautions to avoid ingesting aluminum. Unfortunately, its impossible to completely avoid all aluminum, since its naturally present in nearly all foods. But lithium can help protect your brain against aluminum by helping to chelate it so that it can be more easily removed from the body.25

Although Alzheimers disease and senile dementia arent technically the same, they do share many of the same degenerative features so theres every reason to expect that lithium will help prevent or slow the progression of senile dementia too.


From nutritherapy-The orotic form of lithium is transported directly to the intracellular membranes of mitochondrial, lysosomes and the glia cells. It stabilizes the lysosomal membranes and prevents the enzyme reactions that are responsible for sodium depletion and dehydration effects of other lithium salts making it a far superior source than the pharmaceutical forms of lithium and far safer too. Lithium protects against the shrinkage of the prefrontal cortex and the reductions in glial cell density, which are otherwise seen in bipolar depression. It may provide the growth-promoting support necessary to restore, enhance, and maintain normal synaptic connectivity.

Lithium has been found to be one of the most effective treatments for manic-depressive illness (bi-polar disorder). Normally these patients are given antidepressant drugs which are known to deplete body stores of L-carnitine and Taurine. These amino acids should be supplemented using several grams daily to ameliorate the adverse side effects of these drugs.

Of course it would be better to avoid these drugs all together and that is what Lithium Orotate enables many to accomplish. This is an important consideration, especially when the therapeutic dose of lithium orotate for cases of severe depression is 150 mg/day (1-2 tablets), compared to 900-1800 mg of the prescription forms. In this dosage range, there are no adverse lithium side effects and no need for blood monitoring.

Recent Lithium Research: Evidence suggests that people with mania or depression may lose brain cells. Lithium may thwart that cell death. A study by Chuang and his colleagues reveals that lithium protects brain cells from being stimulated to death by glutamate, one of the many chemicals that transmit messages in the brain. Their new data suggest that lithium may calm overexcited areas of the brain or, more provocatively, preserve the life of brain (glial) cells whose presence guards against manic depression. It was also reported that it does take a week or two for the neuro-protective effects of lithium to fully take place.

Lithium supplementation shields neurons and intact brains alike against insults as wide-ranging as excessive doses of anticonvulsant medications, deprival of growth factors or essential electrolytes, the Alzheimers protein beta amyloid, and neurotoxins like oubain, quinolinic acid, and MPP+. Lithium supplements decrease the number of brain cells killed by experimental strokes by 40%, and help the animals to recover their balance and motility more quickly. Remarkably, most of these benefits can be gained even after the model stroke is over. Lithium supplements also aid brain regeneration in animal models of Huntingtons disease.

Lithium Orotate provides defense against excitotoxicity (the frying of brain cells by over stimulation). It does this through precision modulating of the N-methyl-D-aspartate (NMA) receptors response to the stimulatory neurotransmitter glutamate. Glutamate binds to a cell surface protein of the NMDA receptors when it excites a cell. Normally, activation of the NMDA receptor by glutamate triggers an influx of calcium ions, setting off a signaling cascade inside cells. However, cells treated with lithium let in far less calcium when exposed to glutamate. Lithium has a push/pull effect on glutamate raising its levels when they are too low and lowering them when they are too high by modulating it reuptake. This balancing act helps to prevent both excessive stimulation (which kills brain cells and inadequate activation of the NMDA receptor which interferes with normal activation and function of nerve cells needed for mood and memory. In people with manic depression, lithium may correct a dysfunction of the NMDA receptor by limiting calcium influx, speculates Chuang.

Lithium Orotate increases levels of the major neuroprotective protein bcl-2 in brain cells. Bcl-2 is a cell survival protein which inhibits cell death in response to a wide range of neurotoxins and cellular stressors, including large doses of cortisol (prednisone), ionizing radiation, free radicals, chemicals that deplete brain cells of the antioxidant reduced glutathione (GSH), and deprivation of crucial brain growth factors. Beyond its abilities to protect brain cells from toxic assault, its now emerging that lithium, acting through bcl-2, also helps to regenerate nerve cells, activating a genetic program (the ERK/MAP kinase pathway) that stimulates the growth of new axons and promoting the sprouting of new neurites (the branching tips of nerve cells which bridge the gap between neurons).

And perhaps most excitingly of all, lithium inhibits the activity GSK-3, an enzyme, which promotes the formation of the key pathological features of brains under assault by Alzheimers disease. GSK-3 is involved in forming the tangles that characterize the brains of Alzheimers patients. So damping down the activity of GSK-3 would be expected to reduce tangle formation. And in animals given a gene that causes them to overproduce the precursor to the brain-wrecking amyloid beta protein, lithium supplements interfere with the formation of amyloid beta peptides and prevent plaque formation. This has led to the recommendation that the use of lithium in experimental trials aimed to ameliorate neurodegeneration in Alzheimers disease should be considered.




This stack is so cheap if bought in bulk and is a practical augmentation too um .... ANything

500-750mg agmatine sulphate TiD
400-800 mcg huperazine ABiD
2000mg magnesium l threonate / magtein ( I take 2. X 2000 mgs BiD. )
120-50 mgs lithium orotate before bed

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If I'm using magtein I'm also using mag ox but due too my TMG consumption I've always felt pretty good about magnesium oxide (I mention this because one 2000mg magnesium l threonate serving has between 36-38% of your daily elemental magnesium , now for me in my mind if the point is too supplement in the first place , I can't be happy with the assumption that lowered daily values for mg intake is somehow mediated by what the magnesium is bonded too . A deficit is a deficit I'd rather use the harder too obtain $$ magnesium l threonate then any other for a magnesium supplement however I don't wanna be correcting deficits with it instead of reaping the nootropic rewards

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I'm just going too use this thread as my rX/nootropic treatment guideline / boo assay thread for all interested


Back to List |HomeEncyclopedia(-)-1-(Benzofuran-2-yl)-2-propylaminopentane
(-)-1-(Benzofuran-2-yl)-2-propylaminopentane



(-)-1-(Benzofuran-2-yl)-2-propylaminopentane
Systematic (IUPAC) name
(-)-1-(Benzofuran-2-yl)-2-propylaminopentane
Identifiers
CAS number ?
ATC code ?
PubChem ?
Chemical data
Formula C16H23NO
Mol. mass 245.37
Pharmacokinetic data
Bioavailability ?
Metabolism ?
Half life ?
Excretion ?
Therapeutic considerations
Pregnancy cat.
?

Legal status
Routes ?
(-)-1-(Benzofuran-2-yl)-2-propylaminopentane ((-)BPAP) is a drug with an unusual effects profile. It can loosely be grouped with the stimulant or antidepressant drug families, but its mechanism of action is quite different.[1][2]

BPAP (along with another similar compound PPAP) is classified as a catecholaminergic and serotonergic activity enhancer. This means that it stimulates the impulse propagation mediated transmitter release of the neurotransmitters dopamine, noradrenaline and serotonin in the brain. However unlike stimulant drugs like amphetamines, which release a flood of these neurotransmitters in an uncontrolled manner, BPAP instead only increases the amount of neurotransmitter that gets released when a neuron is stimulated by receiving an impulse from a neighbouring neuron. So while both amphetamines and BPAP increase the amount of neurotransmitters that get released, amphetamines cause neurons to dump neurotransmitter stores into the synapse regardless of external input, while with BPAP the pattern of neurotransmitter release is not changed, but when the neuron would normally release neurotransmitter, a larger amount than normal is released.[3][4]

Other drugs which produce this effect are the endogenous trace amines phenethylamine and tryptamine, and the neuroprotective MAO-B inhibitor selegiline.[5] However while selegiline is a potent monoamine oxidase inhibitor, BPAP is only a weak MAO-A inhibitor at high doses, and at low doses produces only the activity enhancer effect.

BPAP has been shown to have neuroprotective effects similar to those of selegiline, and has been researched for the treatment of Alzheimer's disease, Parkinson's disease and clinical depression.[6]



References
^ Shimazu S, Takahata K, Katsuki H, Tsunekawa H, Tanigawa A, Yoneda F, Knoll J, Akaike A. (-)-1-(Benzofuran-2-yl)-2-propylaminopentane enhances locomotor activity in rats due to its ability to induce dopamine release. European Journal of Pharmacology. 2001; 421: 181-189.
^ Shimazu S, Tsunekawa H, Yoneda F, Katsuki H, Akaike A, Janowsky A. Transporter Mediated Actions of R-(-)-1-(Benzofuran-2-yl)-2-propylaminopentane. European Journal of Pharmacology. 2003; 482: 9-16.
^ Knoll J, Yoneda F, Knoll B, Ohde H, Miklya I. (-)-1-(Benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain. British Journal of Pharmacology 1999; 128: 1723-1732
^ Oka T, Yasusa T, Ando T, Watanabe M, Yoneda F, Ishida T, Knoll J. Enantioselective Synthesis and Absolute Configuration of (-)-1-(Benzofuran-2-yl)-2-propylaminopentane ((-)BPAP), a Highly Potent and Selective Catecholaminergic Activity Enhancer. Bioorganic and Medicinal Chemistry. 2001; 9: 1213-1219.
^ Shimazu S, Miklya I. Pharmacological studies with endogenous enhancer substances: β-phenethylamine, tryptamine, and their synthetic derivatives. Progress in Neuropsychopharmacology & Biological Psychiatry. 2004; 28: 421-427.
^ Gaszner P, Miklya I. Major depression and the synthetic enhancer substances (-)-deprenyl and (-)-1-(Benzofuran-2-yl)-2-propylaminopentane. Progress in Neuropsychopharmacology & Biological Psychiatry. 2006 Jan;30(1):5-14.

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10mcgs Bpap x 10 daily sounds about right ..... timing is everything and 200 mcgs is definitely more euphoric but is euphoria or long term repression we are looking for ?

 

I usually dose

 

70mcg BID =140mcg BPAP daily

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more on (-)-BPAP

 

(-)-1-(Benzofuran-2-yl)-2-propylaminopentane ((-)-BPAP)^[1] is a drug with an unusual effects profile. It can loosely be grouped with the stimulant or antidepressant drug families, but its mechanism of action is quite different.^[2][3]

BPAP (along with another similar compound PPAP) is classified as a catecholaminergic and serotonergic activity enhancer. This means that it stimulates the impulse propagation mediated transmitter release of the neurotransmitters dopamine, norepinephrine and serotonin in the brain. However, unlike stimulant drugs like amphetamine, which release a flood of these neurotransmitters in an uncontrolled manner, BPAP instead only increases the amount of neurotransmitter that gets released when a neuron is stimulated by receiving an impulse from a neighbouring neuron. So while both amphetamine and BPAP increase the amount of neurotransmitters that get released, amphetamine causes neurons to dump neurotransmitter stores into the synapse regardless of external input, while with BPAP the pattern of neurotransmitter release is not changed, but when the neuron would normally release neurotransmitter, a larger amount than normal is released.^[4][5]

Other drugs which produce this effect are the endogenous trace amines phenethylamine and tryptamine, and the neuroprotective MAO-B inhibitor selegiline.^[6] However, while selegiline is a potent monoamine oxidase inhibitor, BPAP is only a weak MAO-A inhibitor at high doses, and at low doses produces only the activity enhancer effect.

BPAP has been shown to have neuroprotective effects similar to those of selegiline, and has been researched for the treatment of Alzheimer's disease, Parkinson's disease and clinical depression.^[7]

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On BPAP Deprenyl and CAE effecting stacks

 

 

 

Catechol is a chemical, but catechol may also be used as the name of a substituent, where it represents a 1,2-dihydroxybenzene group.

Catecholamines are derived from the amino acid tyrosine.^[2] Catecholamines are water-soluble and are 50%-bound to plasma proteins when they circulate in the bloodstream.

In the human body, the most abundant catecholamines are epinephrine (adrenaline), norepinephrine (noradrenaline) and dopamine, all of which are produced from phenylalanine and tyrosine. Release of the hormones epinephrine and norepinephrine from the adrenal medulla of the adrenal glands is part of the fight-or-flight response.^[3]

Tyrosine is created from phenylalanine by hydroxylation by the enzyme phenylalanine hydroxylase. Tyrosine is also ingested directly from dietary protein. Catecholamine-secreting cells use several reactions to convert tyrosine serially to L-DOPA and then to dopamine. Depending on the cell type, dopamine may be further converted to norepinephrine or even further converted to epinephrine.^[4]

Various stimulant drugs are catecholamine analogues.

 

Structure

Catecholamines have the distinct structure of a benzene ring with two hydroxyl groups, an intermediate ethyl chain, and a terminal amine group. Phenylethanolamines such as norepinephrine have a hydroxyl group on the ethyl chain.

Production and degradation Location

Catecholamines are produced mainly by the chromaffin cells of the adrenal medulla and the postganglionic fibers of the sympathetic nervous system. Dopamine, which acts as a neurotransmitter in the central nervous system, is largely produced in neuronal cell bodies in two areas of the brainstem: the substantia nigra and the ventral tegmental area. The similarly melanin-pigmented cell bodies of the locus ceruleus produce norepinephrine.

Synthesis

Dopamine is the first catecholamine synthesized from DOPA. In turn, norepinephrine and epinephrine are derived from further metabolic modification of dopamine. The enzyme dopamine hydroxylase requires copper as a cofactor (not shown) and DOPA decarboxylase requires PLP (not shown). The rate limiting step in catecholamine biosynthesis is hydroxylation of tyrosine.

L-Phenylalanine

L-Tyrosine

L-Dopa

Epinephrine

Phenethylamine

p-Tyramine

Dopamine

Norepinephrine

N-Methylphenethylamine

N-Methyltyramine

p-Octopamine

Synephrine

3-Methoxytyramine

AADC

AADC

AADC

PNMT

PNMT

PNMT

PNMT

AAAH

AAAH

COMT

DBH

DBH

L-Phenylalanine is converted into L-tyrosine by the enzyme Aromatic amino acid hydroxylase (AAAH), with molecular oxygen (O₂) and tetrahydrobiopterin as cofactors. L-Tyrosine is converted into L-DOPA by the enzyme AAAH with tetrahydrobiopterin, O₂, and ferrous iron (Fe²⁺) as cofactors. L-DOPA is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase (AADC), with pyridoxal phosphate as the cofactor. Dopamine itself is also used as precursor in the synthesis of the neurotransmitters norepinephrine and epinephrine. Dopamine is converted into norepinephrine by the enzyme dopamine β-hydroxylase (DBH), with O₂ and L-ascorbic acid as cofactors. Norepinephrine is converted into epinephrine by the enzyme phenylethanolamine N-methyltransferase (PNMT) with S-adenosyl-L-methionine as the cofactor.

Catecholamine synthesis is inhibited by alpha-methyl-p-tyrosine (AMPT), which inhibits tyrosine hydroxylase.^{[citation needed]}

Degradation

Catecholamines have a half-life of a few minutes when circulating in the blood. They can be degraded either by methylation by catechol-O-methyltransferases (COMT) or by deamination by monoamine oxidases (MAO).

MAOIs bind to MAO, thereby preventing it from breaking down catecholamines and other monoamines.

Function Modality

Two catecholamines, norepinephrine and dopamine, act as neuromodulators in the central nervous system and as hormones in the blood circulation. The catecholamine norepinephrine is a neuromodulator of the peripheral sympathetic nervous system but is also present in the blood (mostly through "spillover" from the synapses of the sympathetic system).

High catecholamine levels in blood are associated with stress, which can be induced from psychological reactions or environmental stressors such as elevated sound levels, intense light, or low blood sugar levels.

Extremely high levels of catecholamines (also known as catecholamine toxicity) can occur in central nervous system trauma due to stimulation and/or damage of nuclei in the brainstem, in particular those nuclei affecting the sympathetic nervous system. In emergency medicine, this occurrence is widely known as catecholamine dump.

Extremely high levels of catecholamine can also be caused by neuroendocrine tumors in the adrenal medulla, a treatable condition known as pheochromocytoma.

High levels of catecholamines can also be caused by monoamine oxidase A (MAO-A) deficiency. As MAO-A is one of the enzymes responsible for degradation of these neurotransmitters, its deficiency increases the bioavailability of these neurotransmitters considerably. It occurs in the absence of pheochromocytoma, neuroendocrine tumors, and carcinoid syndrome, but it looks similar to carcinoid syndrome such as facial flushing and aggression.^[5][6]

Effects

Catecholamines cause general physiological changes that prepare the body for physical activity (fight-or-flight response). Some typical effects are increases in heart rate, blood pressure, blood glucose levels, and a general reaction of the sympathetic nervous system. Some drugs, like tolcapone (a central COMT-inhibitor), raise the levels of all the catecholamines.

[Ultravioletbllc]

more on BPAP but the adverts are edited:

 

(-)BPAP 8000 mcg in 30 ml water = $++++++
10 mcg per drop.
Dosage = 10 drops per day



80 days would equal 100mcg per day (.1mg) - not the same as the deprenyl dose
 

[Ultravioletbllc]

More and lastly On BPAP from Paul Walker as I believe

 

 

 

R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane - (-)-BPAP A chemical for brain health, nootropic potential, mood enhancement and potentially life extension, often compared with Deprenyl.

Below we present a summary of the major research results for (-)-BPAP, taken from published studies in the peer-reviewed literature. In summary:
(-)-BPAP is a powerful catecholaminergic/serotoninergic activity enhancer over 100 times as effective as deprenyl (which it was invented to replace), with a broader spectrum of neurotransmitter enhancement effects and without the negative amphetamine and MOA inhibition side effects. It has been shown to have anti-depression, neurotrophic and brain antioxidative benefits. Moreover, with a better safety profile than deprenyl, BPAP appears to have even more life extension potential than deprenyl although this last is yet untested in any mammal.

Safety, Pharmacology and Interactions

1. "(-)-Deprenyl, the only synthetic enhancer substance in clinical use is known to be a safe, well-tolerated drug. Since (-)-BPAP, ... a deprenyl-derived enhancer substance being free of the MAO-B inhibitory property ... which is ... at least 100-times more potent than (-)-deprenyl, has even a better safety margin than (-)-deprenyl, we may expect that 100-times higher doses of (-)-BPAP than the ones that exert an enhancer effect can be administered without risk of significant side-effects."^R
2. "(-)-BPAP did not show any effects on spontaneous norepinephrine release. Thus, (-)-BPAP did not exert tyramine-like norepinephrine releasing action. ... Furthermore, we demonstrated that (-)-BPAP inhibited tyramine-induced norepinephrine release ... (-)-BPAP, as demonstrated here, has a similar action to (-)-deprenyl ["a blockade of (-)-deprenyl against the 'cheese effect' induced by tyramine"] concerning potential to participate in hypertensive crisis. As (-)-BPAP has an affinity to catecholamine transporters which are also carriers for tyramine, the inhibitory action of (-)-BPAP on tyramineinduced norepinephrine release may be due to its tyramine uptake inhibitory action. In the present study, (-)-BPAP was also demonstrated not to influence spontaneous dopamine release, and to reduce tyramine-induced dopamine release, as was the case for norepinephrine. Thus, (-)-BPAP inhibits the effect of tyramine."^R
3. "in rats ... (-)-BPAP-14C ... was well absorbed after i.p., s.c. and oral treatment and Cmax has been reached at 30 to 60 min following drug administration. A second peak, detected at 4 hours, indicated enterohepatic circulation of the substance. The highest tissue levels ... were reached at 30 min following s.c. treatment. ... A similar distribution profile was observed in the brain regions with a peak level at 30 min. ... is preferentially eliminated through the urine, the secondary route of excretion was the stool. More than 90% of the substance was recovered in the excreta during 72 hours. The t1/2 beta was found to be 5.5 to 5.8 hours. (-)-BPAP was well absorbed and penetrated the brain. Its elimination was fast and enterohepatic circulation was observed in rats."^R
4. "(-)Deprenyl (Selegiline), for the time being the only CAE [catecholaminergic activity enhancer] substance in clinical use free of the catecholamine releasing property, is metabolized to methamphetamine and amphetamine and is also a highly potent and selective MAO-B inhibitor. To get rid of these, from point of view of the CAE effect, disadvantageous properties of the compound, we synthetized [sic] in the early '90s deprenyl analogues not metabolized to amphetamines and free of the MAO inhibitory effect."
   "Our selected reference compound, (-)-BPAP, ... a much more potent enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain than ... (-)-deprenyl ... and a compound structurally unrelated to PEA [phenylethylamine] and the amphetamines, seems to be an especially promising experimental tool for studying the nature and the physiological role of the CAE/SAE [catecholaminergic/serotoninergic activity enhancer] mechanism in the brain. ..."
   "(-)-BPAP, obviously because of its close structural similarity to tryptamine, is a weak, selective inhibitor of MAO-A, but this effect is from pharmacological point of view not significant."^R

Proven Benefits

1. In cultured rat and human cells, which "work under catecholaminergic influence", subjected to hypoxia, "(-)-BPAP and (-)-deprenyl, due to their enhancer effect, exerted a significant cytoprotective effect"^R
2. "in rat mesencephalic slice cultures ... R-(-)-BPAP significantly increased the mRNA and protein levels of BDNF [brain-derived neurotrophic factor], without affecting the level of NT-3 mRNA. In addition, R-(-)-BPAP significantly increased the mRNA level of trkB [a cell receptor], but not that of p75(NTR) [another cell receptor]. These effects of R-(-)-BPAP may result in enhanced BDNF/trkB signaling, and could thus underlie the potential neurotrophic and antidepressant actions of this drug."
   "Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family that plays an important role in regulating survival, differentiation, and functional integrity of central neurons. BDNF interacts with a specific trkB receptor kinase and with a low-affinity receptor p75NTR. Deficiencies of neurotrophins and their receptors are regarded as an important aspect of the pathogenesis of neurodegenerative disorders. Dopaminergic neuronal death in Parkinson's disease has been associated with the depletion of neurotrophins, such as BDNF and nerve growth factor (NGF). Indeed, the levels of neurotrophins, especially BDNF, were markedly reduced in the substantia nigra of Parkinson's disease patients, in whom selective degeneration of dopaminergic neurons is evident. Therefore, pharmacological stimulation of endogenous neurotrophin synthesis is expected to become a useful therapeutic approach for Parkinson's disease. R-(-)-1-(Benzofuran-2-yl)-2-propylaminopentane [R-(-)-BPAP], a potent "catecholaminergic and serotonergic activity enhancer", enhances the electric field stimulation-induced release of catecholamine and serotonin from isolated rat brain stem. Because of its "catecholaminergic and serotonergic activity enhancer" effects, R-(-)-BPAP ameliorates motor deficits in reserpine-treated rats and improves active avoidance behavior in rats under tetrabenazine-induced depression. Therefore, this drug is a promising candidate as a treatment for symptoms of depression as well as for Parkinson's disease. .... Recently, the induction of BDNF/trkB signal was implicated as an important mechanism of action of antidepressants. For example, the infusion of BDNF into the midbrain produces antidepressant-like effects in an animal model of depression. Interestingly, R-(-)-BPAP is reported to produce antidepressant-like activity in rats with tetrabenazine-induced depression. ... Our findings suggest that R-(-)-BPAP, in addition to action mediated by its "catecholaminergic and serotonergic activity enhancer" effect, may serve as a neuroprotective agent for the treatment of progressive neurodegenerative disorders."^R
3. "(-)-Deprenyl, a prototype of the phenylethylamine-derived synthetic enhancer substances, stimulates the catecholaminergic neurons in the brain but is almost ineffective on the serotonergic neurons. R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane, (-)-BPAP, the recently developed tryptamine-derived selective synthetic enhancer substance, is a hundred times more potent enhancer of the catecholaminergic neuronal activity than (-)-deprenyl, and is also a highly potent stimulant of the serotonergic neurons. Evaluation of the peculiar pharmacological profile, the high potency and unusual safeness and tolerability of (-)-BPAP cherish the hope that this compound by itself and in combination with uptake inhibitors may improve the effectiveness of drug therapy in major depression and diminish the number of therapy resistant cases. ... (-)-BPAP, the first tryptamine-derived selective and highly potent synthetic enhancer substance that opens a previously unknown possibility to keep the activity of the noradrenergic, dopaminergic, and serotonergic neurons in the brain on a higher activity level. ... Since (-)-deprenyl is a highly potent and selective inhibitor of MAO-B, a structure-activity relationship study was performed to develop a deprenyl-derived enhancer substance being free of the MAO-B inhibitory property, and (-)-PPAP is at present the reference substance with this pharmacological profile."^R1,R2
4. "(-)-BPAP may block tyramine-induced adverse effects such as hypertensive crisis. The actions of (-)-BPAP on the spontaneous and tyramine-induced dopamine release resembled its effects on norepinephrine release. We conclude that (-)-BPAP is not only catecholaminergic and serotonergic activity enhancer, but also a norepinephrine and dopamine uptake inhibitor and a weak serotonin uptake inhibitor that does not possess a tyramine-like action on catecholamine release, and is an inhibitor of tyramine-induced release of norepinephrine. ... Based on the dopamine deficiency theory, activation of the dopaminergic system by (-)-BPAP may be useful for the improvement of motor deficits in patients with early Parkinson's disease. (-)-BPAP is also expected to improve the non-motor functional deficits such as depression that is observed in Parkinson's disease, is unresponsive to anti-Parkinsonian drugs"^R
5. "in cultured mouse astrocytes ... The amounts of NGF [nerve growth factor], BDNF [brain-derived neurotrophic factor], and GDNF [glial cell line-derived neurotrophic factor] secreted from astrocytes into the culture medium increased by up to 120, two, and seven times higher than those of the control, respectively, by treatment with 0.35 mM (-)-BPAP for 24 h. ... Furthermore, the treatment with (-)-BPAP for 6 h increased the mRNA expression of NGF, BDNF, and GDNF. These results suggest that (-)-BPAP up-regulated neurotrophic factor synthesis in cultured astrocytes."^R
6. "These findings suggested that a "catecholaminergic and serotoninergic activity enhancer" compound, (-)-BPAP, stimulates motor function in rats and improves motor deficits in animal models of Parkinson's disease due to its ability to induce dopamine release."^R
7. "The chemical reactions between (-)-BPAP and .OH were studied ... (-)-BPAP was proved to be a good radical scavenger. It was found that every atom of the benzofuran ring, except carbon 3, was capable of easily trapping the radical, where the most active site was carbon 1 on the furan part. ... Since the single radical trapping products were still radicals, these could trap further radicals by way of cascade without any activation energy. Thus, the double radical trapping products were very stable ..."^R
8. "These findings suggest that (-)-BPAP [has] unique survival activity on cortical neurons through sigma receptors."^R

Potential Benefits

1. "This paper presents that a series of benzofuran derivatives prevented apoptosis induced by an endogenous neurotoxin ... it remains to be clarified whether BPAP derivatives activate transcription factors, such as NF-KB, to induce anti-apoptotic genes. In addition, the relation of the gene induction to catecholaminergic-serotonergic enhancing effects should be further examined to elucidate the mechanism behind neuroprotection by a series of BPAP derivatives."^R
2. "This substance [(-)-BPAP], which is specific and hundreds of times more potent than selegiline, is now the best experimental tool to study the enhancer regulation in the mesencephalon and a promising candidate to significantly surpass the therapeutic efficiency of selegiline in depression, Parkinson’s disease, and Alzheimer’s disease."^R
3. "Antiaging compounds: (-)deprenyl (selegeline) and (-)1-(benzofuran-2-yl)-2-propylaminopentane, [(-)-BPAP], a selective highly potent enhancer of the impulse propagation mediated release of catecholamine and serotonin in the brain."
   "Hundreds of millions of people now die over the age of 80 years primarily due to twentieth century progress in hygiene, chemotherapy, and immunology. With a longer average lifespan, the need to improve quality of life during the latter decades is more compelling. "Aging--The Epidemic of the New Millenium," a recent international conference (Monte Carlo, June 17-18, 2000), showed with peculiar clarity that a safe and efficient drug strategy to slow the age-related decay of brain performance is still missing. This review summarizes the physiologic and pharmacologic arguments in favor of a peculiar lifelong prophylactic medication with reasonable chances to keep in check brain aging and decrease the precipitation of age-related neurological diseases."^R

Additional Related Papers

1. "The recent discovery of the enhancer regulation in the mammalian brain brought a different perspective to the brain-organized realization of goal-oriented behavior, which is the quintessence of plastic behavioral descriptions such as drive or motivation. According to this new approach, ‘drive’ means that special endogenous enhancer substances enhance the impulse-propagation-mediated release of transmitters in a proper population of enhancersensitive neurons, and keep these neurons in the state of enhanced excitability until the goal is reached. However, to reach any goal needs the participation of the catecholaminergic machinery, the engine of the brain. We developed a method to detect the specific enhancer effect of synthetic enhancer substances [(-)-deprenyl, (-)-PPAP, (-)-BPAP] by measuring the release of transmitters from freshly isolated selected discrete brain areas (striatum, substantia nigra, tuberculum olfactorium, locus coeruleus, raphe) by the aid of HPLC with electrochemical detection. To test the validity of the working hypothesis that in any form of goal-seeking behavior the catecholaminergic and serotonergic neurons work on a higher activity level, we compared the amount of norepinephrine, dopamine, and serotonin released from selected discrete brain areas isolated from the brain of sated and food-deprived rats. Rats were deprived of food for 48 and 72 hours, respectively, and the state of excitability of their catecholaminergic and serotonergic neurons in comparison to that of sated rats was measured. We tested the orienting–searching reflex activity of the rats in a special open field, isolated thereafter selected discrete brain areas and measured the release of norepinephrine, dopamine, and serotonin from the proper tissue samples into the organ bath. The orienting–searching reflex activity of the rats increased proportionally to the time elapsed from the last feed and the amount of dopamine released from the striatum, substantia nigra and tuberculum olfactorium, that of norepinephrine released from the locus coeruleus and that of serotonin released from the raphe increased significantly in the hungry rats proportionally to the time of fasting. For example: the amount of dopamine released from the substantia nigra of sated rats (4.62 +- 0.20 nmoles/g wet weight) increased to 5.95 +- 0.37 (P < 0.05) and 10.67 +- 0.44 (P < 0.01) in rats deprived of food for 48 and 72 hours, respectively."^R
2. "In the cultured astrocytes incubated for 24 h with selegiline, the synthesis of NGF [nerve growth factor] and BDNF [brain-derived neurotrophic factor] was significantly enhanced in the concentration dependent manner, with minimum effective concentrations of 4 x 10^-4 and 5 x 10^-4 M, respectively. (–)-BPAP also enhanced the NGF,BDNF andGDNF synthesis, with minimum effective concentrations of 5 x 10^-5, 1 x 10^-5, and 1 x 10^-6 M, respectively."^R
3. "As (-)-BPAP is for the time being the most selective and most potent available stimulant of the enhancer-sensitive midbrain neurons, we prefer to use this compound in examining the mechanism of action of the enhancer substances. This study is an in vivo and ex vivo analysis of the characteristic dose/concentration dependency of the enhancer effect of (-)-BPAP on catecholaminergic and serotoninergic neurons."^R

[ron45]

Ok, where do you get BPAP? Is this a prescription item? I did a brief search and must not have been looking in the right places. Also WAAAAAAAAAaaaaaaaay back, at the beginning of all this you began with agmatine then you were using the word magtine. I am dyslexic so it occurred to me that maybe you or someone at one of the sites, wiki et al…. swapped the letters. Thanks for all the reading interesting stuff…. what I could understand of it.  

 

Ron

[ron45]

HI I went back just now and saw my error. Aren't you glad you aren't dyslexic? Magtine = Mag L theonate.  Wish I weren't 

 

Ron

[Ultravioletbllc]

Lol I was on top of it tho brotha !

[Ultravioletbllc]

I just received my order for neurontins/gabapentin 300mg I plan Bid dosing , more bpap is in the mail as we speak......I'm so excited about the way this stack I'm on is working out

[Ultravioletbllc]

Received a new batch of (-)-BPAP today wich seems highly synergistic with nmda inhibition

Deprenyl
5-mhtf
Nadh or appropriate pre cursory supps
Agmatine
Dlpa
Low dose buprenorphine/naloxone
Nicotine


All of these are synergistic or are potentiated by bpap

[NineLives]

Low dose buprenorphine/naloxone
 

Isn`t this addictive in the "you will get opiate withdrawals sense" ?

I know suboxone is a mixture of bupe+naloxone and there are plenty of reports of its addictive nature.It makes sense since bupe will bind to the mu receptor(and others) as an agonist especially at low doses with higher affinity than naloxone(even fetanyl I think).

 

Anyway, how is the BPAP going? Interesting substance

[Ultravioletbllc]

Yes it is addictive the trick is utilizing a super low dose of it especially if you are using suboxen
I'm talking like 1/2-1mg daily ( as split doses )

But with all the Nmda inhibition idk if tolerance is only lowered or if it's possible that tolerance and habituation are being mediated

The (-)-Bpap trials are going great
One of the most interesting substances I've ever come across

This is what I can tell you about bpap
It is an immediate mood brightener , has a classic dopaminergic stimulation feel too it w/o all the negative sides

It lasts for about 4-5 hours max w/o deprenyl
Effects seem apparent for 6-8 hours on 5mg deprenyl ( and it's looking like I've found the first substitute that's equal in efficacy too traditional ADHD stims in my current stack )
So I'm dosing twice daily

I've tried a variety of other substances on bpap and it enhances a LOT of stuff I'm already taking

Such as

Nadh
Deplin/quarterfolic /5-mhtf
Dlpa
Curcuminoid c3 extract
Agmatine
Phenylpiracetam
Deprenyl


What I'm really interested in is
The changes half life will go through under chronic administration

[NineLives]

Nmda antagonists are great for tolerance and dependency, but they aren`t full-proof, still bupe is potent shit and 400mcg gets people opiate naive high.

 

Nice to know about BPAP, hope it works out longterm. How do you feel your thought process is affected by it? I know classic stims tend to provide focus but blunt abstract thinking after some time using them.  

 

 

[Ultravioletbllc]

Agreed about the opiate naive comment , however I do believe bupe can be used as a treatment for a variety of non opioid dependence classifications


Bpap is very interesting and so far it oddly shares a similar headspace with low dose adderall reminiscent of the first few über euphoric days of d-amp dosing
Without any of the negative side effects so far , the headspace bpap puts me into is definitely a far more open expanse then what I feel confined too on amps , it is also serotogenic and it isn't deprenyl in fact the effects of bpap are apparent the moments after sublingual administration. As far as motivation and drive go bpap is g


I think I'm really interested in switching too D -PA next week

[Ultravioletbllc]

iPhone just Molly whopped me posted half of what I wrote .... Haha I'll continue in a bit , but so far

(-)-Bpap is in the top 10 most effective substances I have ever tried

And I'd go all the way too top 5 if this continues after the first six weeks with no tolerance hurdles or ending of some sort of supra extended. Honeymoon phase ( but I'm well past any normal timeframe for a honeymoon phase with the same effects profile as day 1 only better more that I've really tinkered w/my dose

[Ultravioletbllc]

I'm co-administering it too my gf with bi- polar who recently switched from fluoxetine too
High dose 100 mg bid PicaMilon , 500 mg daily Dlpa , 1000 mg omega 3, 1000mg methylcobalamin , 5-10 mg lithium daily from 120-240 mg lithium orotate, and as much as I feel she needs of Magnesium (as oxide with 500mg betaine too enhance absorption and for trimethylglycines own therapeutic effects) and Agmatine as needed


She has noticed a marked mood brightening effect with the (-)-Bpap

She is not on deprenyl and is still weighing out the pros and cons of the drug and is learning about exactly what Mao-b is before she decides